Pulmonary arterial hypertension (PAH) afflicts patients of both sexes and across a broad age range and is highly lethal, if not promptly diagnosed and appropriately treated. Despite advances in the understanding of its pathogenesis and the development of 14 therapies approved by the United States Food and Drug Administration (FDA) over the past 2-3 decades, it continues to be associated with significant morbidity and mortality. The fundamental premise in this PPG is that PAH is highly heterogeneous regarding clinical parameters including initiating factors, clinical presentation, rate of progression, and response to therapy. Importantly, patient-to- patient heterogeneity, involving the types of pulmonary vascular lesions and the corresponding endotypes (i.e., underlying molecular processes driving the specific disease presentation), has been uncovered by our group and underlies the high complexity of disease pathogenesis. The paucity of investigations of these broader aspects of heterogeneity has resulted in a lack of understanding of specific factors contributing to particular sub- phenotypes of PAH ? negatively impacting the development of more targeted (and individualized) therapies. These limitations manifest in the fact that some patients live many years on currently available treatments ? however without cure of their disease -, while others progress rapidly and inexorably from onset to transplantation or death. This proposal seeks to uncover novel pathogenetic processes linking pulmonary vascular inflammation, remodeling, and molecular underpinnings of pulmonary vascular lesions in PH, while recognizing the key pathological and pathobiological heterogeneity of the disease. The central premise to be tested in this proposal is that early and persistent local, pulmonary vascular-specific activation of complement leads to persistent perivascular inflammation and extracellular matrix changes, thus shaping a feed-forward loop of pro- inflammatory/pro-remodeling perivascular microenvironment, leading to development of PH. This application represents a major step towards identifying new biomarkers and more effective individualized treatments, which are critically needed.